Major Depressive Disorder (MDD)
Major Depression (MD), also referred to as Major Depressive Disorder (MDD), has been recognized by the World Health Organization (WHO) as a major cause of disability. The prevalence has been estimated to about 10% (ranging between 5% in Japan and 16% in the US). Although apparently easy to recognize, MDD is a clinical entity with multiple subtypes (endophenotypes).
Various drug groups with different mechanism of action are available for the treatment of depression. Action mechanisms include, for example, inhibition of serotonin reuptake, inhibition of norepinephrine (noradrenaline) reuptake, inhibition of dopamine reuptake, blockade of presynaptic receptors on serotoninergic neurons and inhibition of an enzyme responsible for degradation of monoamine neurotransmitters. Such a variety of drugs should potentially enable psychiatrists to choose the most beneficial drug or combination of drugs for each individual patient. Still, in everyday clinical practice there is a lack of information about possible symptoms and biomarkers that could characterize patients and that could be used to determine a superior response of one particular class of drug over another.
Selective serotonin reuptake inhibitors (SSRIs) are a class of compounds, which increase the extracellular level of neurotransmitter serotonin by inhibiting its reuptake into the presynaptic neuron. SSRIs are the most frequently prescribed medications for the treatment of MD. However, the efficacy of SSRI treatment in MD is unsatisfactory. It is estimated that approximately one third of patients diagnosed with MD do not achieve or maintain a response to SSRIs.
Currently, antidepressant drugs are administered by a trial and error method. Most commonly prescribed antidepressant medication does not show beneficial effects until about 3 weeks, and the effects reach a maximum after an additional 4-7 weeks. During this time, patients may experience worsening of clinical symptoms and some of them can discontinue the treatment prematurely. As such, to minimise risk and suffering for patients and costs to society it would be valuable to know whether drugs such an antidepressants are likely to be effective before commencing treatment.
Disruption of the Circadian Rhythm is Causative of Neuropsychiatric Disorders
The circadian clock is an internal oscillator identified in all living organisms, which allows the synchronisation of biological function to the light-dark cycle (Ko & Takahashi 2006). In mammals, including humans, this function is performed by a population of neurons located in the hypothalamus, the so-called suprachiasmatic nucleus (SCN). The SCN consists of several neuronal populations that display prominent cyclic fluctuations in firing patterns. The activity of SCN networks synchronises the circadian fluctuations in physiological functions, including hormonal and autonomic regulation of metabolism with the dark-light cycle (see (Leliayski et al. 2014; Kiessling et al. 2010; Albrecht & Oster 2001). The most important input that is able to reset the circadian clock and synchronise it with an externally imposed rhythm is light. Thus, in addition to merely keeping the pace, the SCN function also has a degree of plasticity/adaptability. The regular distribution of activity and resting/sleep periods is an example of output of the circadian clock (Hu et al. 2009). The cyclic expression of clock genes is present and functional in all tissues and cells, for instance, human skin fibroblasts, and can be studied in ex vivo preparations, such as primary cell cultures (Welsh et al. 2004; Brown et al. 2005). Importantly, features of circadian rhythms, while neural in origin, are carried over to cultured fibroblasts in the form of clock genes. At the subcellular level, the core of the molecular clock consists of a network of transcription factors, referred to as the clock genes, engaged in interlocking feedback loops (see review by (Ko & Takahashi 2006). The cyclic function of the clock maintains a large degree of adaptability by integrating information on metabolic status and level of activity with environmental cues (e.g., ambient light intensity) in order to stablilise the 24 h periodicity.
In mammals, for example, humans, shifting or other disruption of the circadian rhythm is causative of or associated with certain pathological states, including among them, jetlag, many neuropsychiatric disorders, such as depression, schizophrenia, ADHD, sleep disorders, such as excessive daytime sleepiness or insomnia and infertility.
The connection between circadian rhythms and major depressive disorder (MDD) is supported by the following lines of evidence:                1) mutations in clock genes are associated with depression (MDD, SAD, as well as sporadic depressive episodes) (Partonen et al. 2007; Lavebratt et al. 2010; Albrecht 2013)        2) tampering with normal circadian rhythms (e.g., shiftwork) increases the risk of developing MDD or precipitates the recurrence of MDD episodes (Scott et al. 1997)        3) seasonal affective disorder (SAD) occurs during winter, and is triggered by short light phase during winter months. In animal models, exposure to either continuous darkness or continuous light for extended periods of time leads to depression-like behavior (Tapia-Osorio et al. 2013)        4) therapeutic approaches aimed at restoring/resetting/regulating the circadian rhythms are most often effective in controlling mood. Moreover, treatment with melatonin (a hormone secreted by the pineal gland only during the dark phase, and controlled by direct input from the retina), or agomelatine (a melatonin receptor agonist with established antidepressant effects) are effective mood stablilizers (Mairesse et al. 2013; Marrocco et al. 2014)        
A range of factors such as stress, malnutrition and exposure to drugs or chemicals may interfere with critical perinatal developmental periods and have adverse consequences later in life. For example, adverse perinatal events (leading to in utero growth retardation, e.g., from exposure to excess stress hormones) have been shown to increase the risk of metabolic and neuropsychiatric diseases (Harris & Seckl 2011; Maccari et al. 2014). Animal models can be used to study the development, diagnosis and treatment of diseases that have a neurodevelopmental origin, including depression. In addition, pharmacoresponse to a range of drugs can also be studied in such animal models of disease.
Accordingly, there is a need in the art to predict whether drugs, such an antidepressants, are likely to be effective before commencing treatment. There is also a need in the art for agents and methods for diagnosing disorders that are linked with abnormal circadian rhythm.